Vinorelbine and 5-fluorouracil bolus and/or continuous venous infusion plus levofolinic acid as second-line chemotherapy for metastatic breast cancer: an analysis of results in clinical practice of the Gruppo Oncologico Italia Meridionale (GOIM).

BACKGROUND: This retrospective study evaluated the activity and toxicity profile of a regimen of vinorelbine and 5-fluorouracil with levofolinic acid, given to a large series of patients with recurrent or refractory metastatic breast cancer after first-line chemotherapy. PATIENTS AND METHODS: Overall, 286 evaluable patients were included in the analysis. Two chemotherapy schedules were reviewed: a) the bolus regimen consisted of levofolinic acid 100 mg/m2 and 5-fluorouracil 375 mg/m2, both administered i.v. on days 1,2 and 3, plus vinorelbine 25 mg/m2 i.v. bolus on days 1 and 8 every 3 weeks; b) the infusional regimen of levofolinic acid 100 mg/m2 given as a 2-hour infusion, followed by 5-fluorouracil 400 mg/m2 i.v. bolus and by 5-fluorouracil 600 mg/m2 administered as 22-hour continuous venous infusion (c.v.i) for 2 days, plus vinorelbine i.v. bolus on days 1 and 8. RESULTS: Overall, twelve patients achieved a complete response (4%; 95%CL 2%-7%) and 115 patients showed a partial response (40%, 95%CL 34%-46%), for an overall response rate of 44% (95CL 39%-50%). Sixty-one patients had stable disease (21%) and 98 patients progressive disease (34%). The tumor growth control rate was 63% (95%CL 60%-71%). Patients with soft tissue metastases as the dominant disease showed the highest response rate (56%), followed by viscera (48%) and bone (33%). The difference in response rate between patients with dominant visceral disease versus those with dominant bone disease was statistically significant (p=0.038). Patients treated with the bolus schedule achieved a 40% overall response rate with a 5% complete response rate, while those who received the infusional regimen had a 48% overall response rate with a 5% complete response rate. This difference was not statistically significant (p=0.164). The overall median duration of objective responses was 8.3 months (range 4-14 months), median time to progression of the all series was 6.1 months (range 2-24 months) and the median overall survival was 14.6 months (range 3-32). There was a statistically significant difference in survival among responder and non-responder patients (p=0.0009). CONCLUSION: The results of this large off-trial analysis confirmed the clinical activity and adverse-event profile reported in controlled clinical trials of the vinorelbine/ 5-fluorouracil with levofolinic acid regimen in clinical practice. This combination regimen was active with a low toxicity burden and, therefore, represents a good therapeutic choice for patients who require second-line chemotherapy.

Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale.

PURPOSE: we carried out a phase III randomized trial to compare vinorelbine-cisplatin regimen to gemcitabine-cisplatin regimen, and to a sequential administration of gemcitabine-ifosfamide followed by vinorelbine-cisplatin or the opposite sequence of vinorelbine-cisplatin followed by ifosfamide-gemcitabine according to the 'worst drug rule' hypothesis in patients with locally advanced unresectable stage IIIB or metastatic stage IV non-small cell lung cancer. The primary endpoint was survival parameters, while secondary endpoints included analysis of response rates and toxicity. PATIENTS AND METHODS: patients were randomized to receive: (a) gemcitabine 1000 mg/m(2) on days 1, 8 and 15 plus ifosfamide 1500 mg/m(2) on days 8-12 with mesna uroprotection (GI regimen) followed by vinorelbine 25 mg/m(2) on days 1 and 8 plus cisplatin 100 mg/m(2) on day 1 (GI --> VC regimen); (b) the opposite sequence (VC --> GI); (c) vinorelbine plus cisplatin as above described (VC regimen); or (d) gemcitabine 1400 mg/m(2) on days 1 and 8 plus cisplatin 100 mg/m(2) on day 8 (GC regimen). All regimens were given every 4 weeks. All patients were chemotherapy naive and had a ECOG PS 0-2. RESULTS: 400 patients were enrolled into the trial. Interim analysis after inclusion of 243 patients showed that ORR were 19% in the GI --> VC arm, 32% in the inverse sequence arm (CV --> GI), 42% in the VC arm, and 30% in the GC arm. The VC arm was statistically superior over the GI --> VC arm (p = 0.0074), but not over the other regimens. Median TTP was 3.1 months in the GI --> VC arm versus 5.0 months in the VC --> GI arm (p = 0.014). For these reasons the GI --> VC and VC --> GI arm were closed since the 'worst drug rule' hypothesis was rejected. Accrual in the VC and GC arms continued up to 140 and 138 patients respectively. Final ORR were 44% for the VC regimen (4 CR), and 34% for the GC regimen (1 CR). This difference was statistically significant (p = 0.032). OS was 9.0 and 8.2 months, respectively, with no statistically significant difference. The 1-year survival rate was 24 and 20%, respectively for VC and GC regimens. As expected the incidence of phlebitis was higher in the VC arm, while thrombocytopenia, flu-like syndrome and asthenia were more frequent in the GC arm. CONCLUSIONS: the results of this trial indicate that the combination of vinorelbine and cisplatin and that of gemcitabine and cisplatin are equivalent in terms of median TTP and OS, although the vinorelbine-cisplatin regimen is associated with a higher ORR. Both regimens may be considered as reference treatments for future studies. Moreover, our data reject the 'worst drug rule' hypothesis of sequential treatments in NSCCL at least with the combination used in this study.

Pegylated liposomal doxorubicin with vinorelbine in metastatic breast carcinoma. A phase I-II clinical investigation.

A multicenter phase I-II trial was carried out with the aim of identifying the dose-limiting toxicity and the maximum tolerated dose of vinorelbine (VNR) in combination with pegylated liposomal doxorubicin at a dose of 20 mg/m(2) every 15 days in patients with metastatic breast carcinoma. In the phase I part of the trial, VNR was given at a dose of 20 mg/m(2) every 15 days to a group of 3 patients. In absence of unacceptable toxicity, VNR was escalated to 25, 30, and 35 mg/m(2) for subsequent groups of 3 patients, until the dose-limiting toxicity was reached. No case of palmar-plantar erythrodysesthesia was recorded in these patients. Grade 4 neutropenia, grade 3 thrombocytopenia, and grade 3 mucositis were the dose-limiting toxicities recorded in patients treated with VNR 35 mg/m(2). These side effects caused a substantial decrease in programmed dose intensity. Therefore 30 mg/m(2) was considered the maximum tolerated dose of VNR in combination with pegylated liposomal doxorubicin 20 mg/m(2), both given every 15 days. These dosages were employed for the treatment of further 18 patients included in phase II of the study. The overall response rate, calculated according to an intention to treat analysis, was 63% (95% CI: 44-80%), with 2 patients achieving a complete response. The median time to progression was 7.0 months or more (range 2-14 months). Median duration of objective responses was 8.4 months or more. The duration of the 2 complete responses was 9 and 14 months, respectively. Median duration of survival was 16.0 months or more (range from 4.0 to >or=24.0). Toxicity was generally mild and easily manageable. Neutropenia and mucositis were the most frequently recorded side effects. A case of palmar-plantar erythrodysesthesia was recorded in phase II of the study. In conclusion, the maximum tolerated dose of VNR in association with pegylated liposomal doxorubicin is 30 mg/m(2) on a bimonthly schedule. Moreover, the combination of VNR and pegylated liposomal doxorubicin is active against metastatic breast carcinoma and is associated with a good toxicity profile. Further studies with this combination regimen are warranted.